1. Field of the Invention
This invention relates to psoralen compounds, and more particularly to 5'-methyl psoralens synthesized from coumarin derivatives having a common hydroxycoumarin precursor.
2. Prior Art
Psoralens are the linear isomers of the furocoumarin family and they occur naturally in certain fruits and seeds, e.g., Ammi majus and Psoralea corylifolia. Extracts of these fruits and seeds have been used since ancient times as dermal sensitizing agents in the treatment of vitiligo. Topical application of psoralen extracts, followed by irradiation with light, results in a stimulation of melanin production, thus producing a dermal "tanning" effect.
In recent years, psoralens have been utilized in the photo-chemotherapy of psoriasis. In such treatment, psoralens are administered orally or topically to a patient. Subsequently, the skin is exposed to ultra-violet radiation. A high percentage of remissions of the disease occur after such treatment.
With increasing study of, and interest in, molecular biology, the psoralens have been investigated with respect to their ability to form covalent bonds with nucleic acids. Because of their planar structure, psoralens can intercalate between the base pairs in the double helix molecular structure of nucleic acids. Upon irradiation with light of the proper wavelength, the psoralens may form covalent bonds with pyrimidine nucleotides that occur as integral entities of nucleic acid strands. Achieving covalently bonded psoralen bridges or crosslinks between the nucleic acid strands of the double helix presents another tool for use in studying, in vivo, secondary structures of nucleic acids. In addition, the psoralens provide a means for inactivating viruses for the purpose of vaccine production, and also as potential chemotherapeutic agents. The covalently bonded psoralens act as inhibitors of DNA replication and thus have the potential to slow down, or stop, the replication process. The covalent bond can only be produced in a two step process by first intercalating the psoralen into the nucleic acid helix, and second by exposing those sites to electromagnetic radiation. Thus, it is immediately apparent that the covalent bonding can be controlled both temporally and spacially.
4,5',8-trimethylpsoralen and its derivatives have drawn particular attention as effective photoreactive cross-linking reagents for nucleic acids. These 5'-methylpsoralens may be synthesized from the readily available hydroxy-coumarins. However, the prior known synthesizers have proceeded only moderately or poorly, and the yields of 5'-methylpsoralen therefrom have been relatively low. For example, one approach has been reported by K. D. Kaufman, J. Org. Chem., Vol. 26, 117 (1961), which utilizes Claisen rearrangement of 7-allyoxycoumarins. The last step thereof requires use of alkali and gives an overall yield from hydroxycoumarin of 28%.
Accordingly, a good and general method for synthesizing 5'-methylpsoralens in high yield has been hiterto lacking.